ESMO 2022 Award Winner Karim Fizazi Discusses Innovations in Genitourinary Cancers

ESMO Congress 2022 is beginning. This year's ESMO Award 2022 goes to a professor at Paris-Saclay University in Villejuif, France: Prof. Dr. Karim Fizazi.

Dr. Fizazi received this year's ESMO Award for his pioneering work in prostate and other genitourinary cancers, such as cancers of the ureter, bladder and testes. He has authored numerous papers that revolutionized treatment approaches for prostate and testicular cancer. Here, he discusses the future of treatment for urinary tract cancers. Below is a translation of the ESMO team's interview with him.

You have led studies such as LATITUDE and PEACE-1 that changed the outlook for prostate cancer. What do you see as the key to achieving breakthroughs that make a difference?

Many of my research findings took years to bear fruit, so I believe in perseverance and patience. Both trials confirmed my hypothesis of giving intensive treatment in the first line. This better controls disease worsening, increasing complexity and resistance to castration (testosterone suppression), thereby prolonging survival. I was fortunate to lead these two phase-III trials.

LATITUDE, published in the NEJM in 2017, was the first trial to establish the role of a new-generation hormone therapy, abiraterone, added to conventional hormonal treatment to improve overall and progression-free survival in men with newly diagnosed metastatic (stage 4), castration-sensitive prostate cancer.

More recently, the PEACE-1 trial showed that triple therapy with testosterone suppression, docetaxel and abiraterone improved overall survival and radiographic progression-free survival in men with newly diagnosed metastatic castration-sensitive prostate cancer. It was published in the Lancet in 2022.

In parallel, I led the trial establishing the role of the androgen receptor antagonist darolutamide in improving metastasis-free and overall survival in nonmetastatic castration-resistant prostate cancer: ARAMIS, published in the NEJM.

Looking back at these achievements, I believe the central strategy in my work has been to understand disease processes and simplify complex mechanisms—in other words, to identify the key drivers of carcinogenesis and how to target them. One thing has become clear during my time in oncology: not every treatment strategy will work in every patient, and we need to personalize treatment according to cancer subtypes and the individual.

How Has Management of Other Genitourinary Cancers Evolved?

Advances in testicular cancer treatment since the 1980s have resulted in cures for most men with early-stage disease and a large proportion of those with metastatic disease. However, even in the early 2000s, a group of patients with metastatic disease and a poor prognosis remained at risk of relapse and/or death despite surgery followed by the contemporary standard three-drug chemotherapy regimen of bleomycin, etoposide and cisplatin (BEP). Despite numerous randomized trials of alternative regimens, outcomes remain unsatisfactory for these patients with poor-prognosis advanced germ cell tumors. My research team and I therefore began exploring another way to address the problem. We found that the decline in tumor markers alpha-fetoprotein and human chorionic gonadotropin after 3 weeks of chemotherapy predicted treatment response. A subsequent trial, published in the Lancet in 2014, showed that intensifying treatment with six-agent dose-dense chemotherapy improved progression-free survival in patients whose tumor markers did not fall as expected after 3 weeks of BEP. More importantly, the risk of death was reduced by 30% in these men receiving dose-dense chemotherapy, while side effects were reversible.

What Are the Current Unmet Needs in Treating Genitourinary Tumors?

Over the past decade, treatment strategies for metastatic castration-sensitive prostate cancer have evolved from one agent to two and now three together, using the most effective treatment in the first line. Yet unmet needs remain.

Rather than adding a fourth agent, I think we need a detailed study of these patients to design the best strategy for each subgroup. This is the purpose of the PEACE-6 platform of randomized trials. Different trials will explore treatments for subgroups such as oligometastatic disease (few metastases), vulnerable patients such as those in their 80s and 90s, and patients responding well or poorly after several months of systemic treatment. In the latter two groups, it would be useful to determine whether treatment can be reduced in good responders and whether intensive treatment is a good option for those responding poorly to ongoing therapy.

There is also an urgent need to find new targets and treatments for patients in whom current therapies have failed. My group is investigating ODM-208, a nonsteroidal, selective inhibitor of the CYP11A1 enzyme, suppressing the synthesis of all steroid hormones and their precursors. In some patients, a mutated androgen receptor in tumor cells makes them sensitive to other steroid hormones, such as progesterone or glucocorticoids, rather than androgens. Androgen-targeting agents are therefore ineffective in these patients, but ODM-208 was developed to block steroid hormone production and overcome this resistance mechanism.

What Major Developments Do You Foresee Over the Next Few Years?

I think there will increasingly be a shift toward earlier systemic treatment for genitourinary cancers in both men and women. The key is that strategies to prevent recurrence are easier to implement when cancer is at an early stage. I also believe advanced genitourinary cancers will be treated according to tumor biology rather than cancer type, reflecting changing approaches elsewhere in oncology. Unfortunately, treatment funding is a growing concern. I believe the countries and companies represented at the ESMO Congress, together with politicians, must collaborate to find pragmatic solutions so that research findings and their benefits are affordable for all patients.

*

Manage preferences to view external content